Bibliographic details of the publications referred to by author in this specification are collected at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
Cervical carcinoma is one of the most common tumors affecting women world-wide, both in incidence and mortality, with approximately 471,000 new cases diagnosed and about 200,000 women die of the disease annually. (Pisani, et al., 1993 and 1997). In 1994, an estimated 15,000 women in the U.S. were diagnosed with invasive cervical carcinoma and approximately 4600 women died from this disease in the year despite remarkable progress made in screening (Boring et al., 1994). In 1995, the incidence increased to 15,800 cases and 4800 deaths in the U.S. (Wingo, et al., 1995).
Cervical carcinoma has its origins at the squamous-columnar junction either in the endocervical canal or on the portio of the cervix. The precursor lesion is dysplasia or carcinoma in situ (cervical intraepithelial neoplasia [CIN]), which can subsequently become invasive cancer. This process can be quite slow. It is proposed that 50% of dysplastic lesions disappear without treatment and 10% of dysplastic lesions reach the final stage of the intra-epithelial lesion prior to invasion of subjacent tissue. Only 2% of the total number of dysplasias progress beyond this intra-epithelial carcinoma to frank invasive cancer (Ostor, 1993; Duggan, 1998). However, longitudinal studies have shown that in untreated patients with in situ cervical cancer, 30-70% will develop invasive carcinoma over a period of 10-12 years. Only in about 10% of patients, lesions can progress from in situ to invasive in less than a year (Gustafsson, et al., 1989; Van Oortmarssen, et al., 1991).
With reference to cell types, cervical cancer can be classified into squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma and small cell carcinoma. Cellular Classification Squamous cell (epidermoid) carcinoma comprises approximately 80%, while adenosquamous and small cell carcinomas are relatively rare. However, among malignancies of the uterine cervix, the percentage of adenocarcinomas seems to have increased in recent reports, from 4.9-20% (Berek, et al., 1981; Goodman et al., 1989; Vizcaino, et al., 1998). Controversy remains over whether or not adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix (Steren et al., 1993). There are conflicting reports regarding the effect of adenosquamous cell type on outcome (Gallup et al., 1985; Yazigi et al., 1990). A report demonstrated that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts suggesting that any adenomatous differentiation may confer a negative prognosis (Bethwaite et al., 1992). A study of patients with known invasive squamous carcinoma of the cervix found that over-expression of the c-myc oncogene was associated with poorer prognosis significance in early cervical carcinoma (Strang et al., 1987).
It is estimated that more than 6 million women in the U.S. have human papillomavirus (HPV) infection. Epidemiological studies convincingly demonstrate that the major risk factor for the development of pre-invasive or invasive carcinoma of the cervix is related to HPV infection. Studies (Brisson et al., 1994) suggest that acute infection with HPV types 16 and 18 conferred a one to 16.9-fold risk of rapid development of high-grade CIN. This far outweighs other known risk factors such as high parity, increasing number of sexual partners, young age at first intercourse, low socioeconomic status and positive smoking history (Schiffman et al., 1993; Brisson et al., 1994). Although molecular techniques for the identification of HPV DNA are highly sensitive and specific, proper interpretation of these data is important. Some patients with HPV infection appear to be at minimal increased risk for development of cervical preinvasive and invasive malignancies while others appear to be at significant risk and candidates for intensive screening programs and/or early intervention. However, use of a positive HPV DNA test as the only parameter to dictate more in-depth evaluation of the patient may lead to unwarranted and ineffective treatment and/or unnecessary patient anxiety. Conversely, current technology may be too insensitive to detect small amounts of potentially tumorigenic HPV types leading to a false sense of security. Clearly the present recommendation for patients with an abnormal cervical cytology of a high-risk type (Bethesda Classification) should be thoroughly evaluated with colposcopy and biopsy. However, these tests are expensive and can be invasive.
Uterine cervical carcinogenesis has been recognized as a multi-stage process in which human papillornavirus (HPV) infection and other factors, such as somatic genetic alterations play a decisive role in the development of malignant cancer. The accumulation of cytogenetic abnormalities and chromosome structural aberrations or allele loss may lead to the selection of the final tumor phenotype, consistent with the long time that occurs between initial infection and tumor appearance (Herrington et al., 1995; Lazo, 1999).
Identification of these genes can be used for the cancer diagnosis and also to help stratify women into follow-up and treatment groups.
The prognosis for cervical cancer is markedly affected by the extent of disease at the time of diagnosis (Anton-Culver, et al., 1992). Among the major factors that influence prognosis are stage, volume and grade of tumor, histologic type, lymphatic spread, and vascular invasion (Werner-Wasik, et al., 1995). However, the molecular pathways leading to cervical dysplasia remain poorly understood. To gain a global view of the molecular events leading to turnour progression, the inventors have employed differential gene display as a systematic method to compare gene expression in human cervical cancer and matched normal tissues.
In work leading up to the present invention, the inventors identified differentially expressed DNA sequences which have corresponding RNA accumulated to higher levels in various stages of human cervical cancer. Activation of some of these genes in the early clinical stages of cervical cancer suggests their participation in pathways involved in the onset and/or progression of cancer providing diagnostic markers for the cervical cancer and targets for therapeutic intervention.